Interpretive Summary: Problems arising from infection of the lungs are very similar between humans and sheep. Infections are often complicated by the rapid development of breathing difficulties, poor air exchange in the lungs and subsequent strain on the heart to pump blood through the body. Bacterial extracts called endotoxins are important tools to understand how disease causes these lung problems because one can administer these endotoxins to experimental animals and record and measure specific responses as a model of the actual bacterial disease without actually infecting the animal with the organism. We used endotoxin infusions into sheep to model the lung response to diseae and measure and determine how hormones of the immune system called cytokines affect the outcome of disease. When endotoxin was infused into sheep, a cytokine called tumor necrosis factor (TNF) was released. The severity of the lung injury and increase in lung blood flow resistance was highly correlated with the increase in TNF after endotoxin. The data suggest that strategies that can limit TNF production during infection may favorably influence the outcome and survival to the infection with regard to lung function.

Technical Abstract:
We studied changes in cardiovascular and pulmonary function during prolonged endotoxemia in conscious sheep. Sheep with chronic lung lymph fistulas received a 12 h infusion of E. coli endotoxin (10 ng/kg.min) followed by a 12 h recovery period. Supportive therapies were withheld. Prolonged endotoxemia without vascular volume support caused systemic hypotention associated with reduced cardiac output and increased vaascular resistance, pulmonary hypertension, and acute lung injury with progressive respiratory failure. Plasma TNF concentrations increased transiently. Sustained pulmonary hypertension and increased pulmonary and systemic vascular resistances contributed to poor outcome in 9 of 34 sheep (26 %). Plasma TNF concentrations were significantly greater in survivors with sustained pulmonary hypertension and in nonsurviving sheep than in surviving sheep without hypertension. Endotoxin (1 ng/ml) increased neutrophil expression of TNF in vitro. Addition of interleukin-6 prevvented this response. Synthesis and release of TNF may be an important proximal event influencing the development of sustained pulmonary hypertension and progressive respiratory failure with endotoxemia. IL-6 may contribute to the phasic nature of the TNF response.